Therapeutic compound and process of making the same.



ERNST HUG, OF GRENZACH, GERMANY, ASSIGNOR TO HOFFMANN-LA ROCHE CHEMI-GAL WORKS, OF NEW YORK, N. Y., A CORPORATION OF NEW YORK.

THERAPEUTIC COMPOUND AND'PROGESS OF MAKING- THE SAME.

No Drawing.

To all whom it may concern: I

Be it known that I, ERNST HUG, a cltizen of Switzerland, and a residentof Grenzach,

narcotic and toxic effects, mixtures of alkaloids of the opium group,for instance a mixture of morphin and narcotin, surpass morphin alone.In order to .take advantage of this observation for therapeutic purposesthe two alkaloids, morphin and narcotin, were brought into the conditionof double salts by the use of diand poly-basic acids. The best resultsin such cases were observed to take place when the double saltscontained the two alkaloids in about equal parts. The discoveryunderlying the present applica-. tion is that of a double salt of theopium group of alkaloids based upon the use of mono-basic acids asagainst double salts of the dior poly-basic acids. The process,producing these salts of mono-basic acids of the opium group ofalkaloids is newin itself and results in the production of a crystallinedouble salt not heretofore known to science.

The process constituting my invention consists, speaking generally, inevaporating solutions of mixtures of both salts derived from halogenacids, for example in equimolecular amounts, and in crystallizing outthe double salt'from dilute alcoholic solutions, or from alcohol towhich ether has been added. The double salts separate out in the form ofbeautifully crystallized bodies easily soluble in cold water, morediflicultly soluble in alcohol and insoluble in ether.

The following examples illustrate the process more fully, it being ofcourse understood that they are to be regarded merely as illustrative ofm invention:

Example I: 3 5 grams of crystallized morphin hydrochlorid and 449 gramsof dried narcotin hydrochlorid are dissolved in 5000 cubic centimetersof water and the solution, if necessary, is filtered. The solu-Specification of Letters Patent.

Patented Aug. 12, 1913.

Application filed February 8, 1913. Serial No. 746,988.

' .tion is now subjected to a strong vacuum and then treated with an,equal.volume of alcohol. It is then cooled, whereupon the salt'ls throwndown in the form of uniform, short pr1sms which difier markedly inappearance both from the bundles of capillary, needle-like crystals ofthe morphin hydrochlorid and from the shiny, leaf-like crystals of thenarcotin-hydrochlorid. The double 'compound thus obtained becomes yellowin color and melts without foaming at 200 C. Themorphin-narcotin-hydrochlorid' is very easily soluble in cold water,diflicultly soluble in alcohol and insoluble in ether.

The morphin determination of the product may be made according to themethod of Anneler (Archie fair Pharmazz'e, 1912, vol. 250, p. 180).Analysis of the hydrated salt gave the following values:

Found, Computed.

Example II: 335 grams of codein hydrochlorid and 449 grams of. narcotinhydrochlorid are dissolved in 6000 cubic centimeters of water, thesolution thus obtained is concentrated and brought over to an alcoholicsolution by repeated evaporizations with alcohol. The still hot,concentrated alcoholic solution is treated with other until it begins tobecome cloudy; the double salt then crystallizes out into uniformprisms. The melting point of the doublesalt isdifferent from that of themolecular mixture.

of the components. The mixture begins to decompose at 180 to 185 C.while the double compound decomposes, becoming liquid, at 200 C. Thecodein-narcotin hydrochlorid is. 'very easily soluble in water,diflicult-ly soluble in alcohol and insoluble in ether.

For the purpose of analysis a water solution of thesalt'was treated withammonia and the precipitated narcotin weighed. Computed. as water freesubstance the folalcoholic and, after being moderately concentrated, wastreated with ether. The double salt separated out in'uniform, needle-.lowing values were obtained: 2 Found. Computed.

Narcotin 51.53 52.62

Water (21-1 4.145%- like crystals containing two molecules of water ofcrystallization. The morphin-narcotin-hydrobromid formed dissolvesrather easily in cold water and very easily inhot of theopium group.

water, it is. difiicult to dissolve it in cold alcohol but slightly lessdiflicult in hot alcohol; it is insoluble in ether.

The double salt has no sharply defined meltin point but begins tosoften, meanwhile becoming brown in color, at 170 C. The waterdetermination gave the following results:

Found. Computed.

The determination of morphin, free of water, is accomplished as inExample I.

Found. 32.6%

Computed.

Morphin l 33.2%

It will be seen from the examples that the halogen acids have been used.They are of particular importance and value because the salts derivedtherefrom onaccount of theircapability of being readily dissolved,absorbed and easily handled adds to their therapeutic utility. Theproducts produced by these examples are chemical combinations, eachcomprising two of the alkaloids of the opium group and each one of whichapparently serves to strengthen and modify the other. v

By the expression Opium group as used in this specification and in theclaims I intend to refer to the series of opium alkaloids of whichmorphin may be treated as representative, and of which co dein, the-'ham, narcotin, narceln, papaverln are some of the better known members.

1,oeo,9 54.

What I claim is: v 1. Monobasic acid double salt of alkaloids of theopium group.

2. Halogen acid double salt of alkaloids The process of producing amonobasic a'cld double salt of alkaloids of the opium group, WhlChconsists in crystallizing said double salt from an alcoholic solution ofa mixture of two monobasic acid salts of said alkaloids.

4:. The process of producing a halogen acid double salt of alkaloids ofthe opium group, which consists in crystallizing said double salt froman alcoholic solution of a mixture of two halogen acid salts of saidalkaloids.

5. The process of producing a monobasic acid double salt of alkaloids ofthe opium group, which consists in forming a water solution of a mixtureof two monobasic acid salts of alkaloids of, the opium group and addingalcohol to said solution to crystallize out the monobasic acid doublesalt of said alkaloids. 6. The process of producing a halogen aciddouble salt of alkaloids of the opium group, which consists in formingan alcoholic solution of a mixture of two halogen acid salts ofalkaloids of the opium group and crystallizing out from said solutionthe halogen acid double salt of said alkaloids.

In witness whereof I have hereunto set my hand in the presence of twosubscribing witnesses.

ERNST HUG.

Witnesses: I HEINRICH KUBLI, PETER Mnrzcnn.

